Process for the preparation of phenyltetrazole derivatives

ABSTRACT

A process for the preparation of phenyltetrazole derivatives of formula (II) wherein R and Y are as defined in the disclosure, by direct ortho-metallation of (tetrazol-5-γl)benzene. The compounds of formula (II) are useful intermediates for the preparation of angiotensin II antagonists.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation ofsubstituted phenyltetrazole compounds, useful as intermediates for thepreparation of angiotensin II antagonists.

BACKGROUND OF THE INVENTION

Angiotensin II antagonists are used, for example, in the treatment ofhypertension, anxiety, glaucoma and heart failure. A number of thesecompounds are characterized by a biphenyltetrazole moiety and can berepresented by the following formula (I)

wherein Z is an optionally substituted heterocycle containing at leastone nitrogen atom; or an amido residue.

Preferably, the residue Z has the following meanings, which identifyspecific angiotensin II antagonists:

2-butyl-4-chloro-5-hydroxymethyl-imidazol-1-yl (losartan);

2-ethoxy-7-carboxy-1H-benzimidazol-1-yl (candesartan);

2-butyl-1,3-diaza-spiro[4,4]non-1-en-4-on-3-yl (irbesartan); and

(S)—N-(1-carboxy-2-methylprop-1-yl)-N-pentanoylamino (valsartan).

Key intermediates for the preparation of compounds of formula (I) are2-substituted phenyltetrazoles of formula (II)

in which R is hydrogen, a protecting group or a salifying group and Y isa —B(OR₄)₂ group, wherein each R₄ is independently hydrogen or C₁-C₆alkyl; or a ZnX group, wherein X is a halogen atom selected fromchlorine, bromine and iodine.

A number of processes for the preparation of the compounds of formula(II) are known. For example, the process disclosed in U.S. Pat. No.5,039,814 or in WO 93/10106 comprises the ortho-litiation of thephenyltetrazole and the subsequent transmetallation reaction. The maindrawbacks of said process resides in the need to use an organo-lithiumcompound, i.e. a compound which requires specific safety precautionswhen used on an industrial scale, due to its high flammability andreactivity.

WO 99/01459 partly solves the problems deriving from the use oforgano-lithium compounds by reacting a compound of formula (III)

in which R is as defined above,

with a Grignard reagent of formulaR₁—MgX

in which R₁ is C₁-C₆ alkyl or benzyl and X is as defined above;

in the presence of catalytic amounts of a secondary amine, which acts asa disaggregant of the Grignard reagent;

thereby obtaining a compound of formula (IV)

wherein R and X are as defined above. This compound is however hardlyreactive and cannot be used as such in “cross-coupling” reactions forthe preparation of compounds of formula (I). Therefore, this compound issubjected to a transmetallation reaction, according to known procedures,to obtain a compound of formula (II) as defined above, which is muchmore reactive. The use of a Grignard reagent, compared with anorgano-lithium compound, is undoubtedly safer, but still potentiallydangerous on an industrial scale and still requires specific procedures.

It is therefore evident that there is still need for an alternativeprocess for the preparation of compounds of formula (II), in particulara process which does not require the use of Grignard reagents.

DETAILED DESCRIPTION OF THE INVENTION

It has now been found a process for the preparation of compounds offormula (II) which does not involve the use of Grignard reagents and istherefore safer; furthermore, this process is more advantageous from theindustrial point of view as it provides higher yields, is less costlyand involves less preparation steps.

Therefore, the present invention relates to a process for thepreparation of compounds of formula (II)

wherein R is hydrogen, a protecting group or a salifying group and Y isa —B(OR₄)₂ group, in which each R₄ is independently hydrogen or C₁-C₆alkyl; or a —ZnX group, wherein X is a halogen atom selected fromchlorine, bromine and iodine;

which comprises the reaction of a compound of formula (V)

wherein R is as defined above and R₂ and R₃, which can be the same ordifferent, are straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl,trialkylsilyl, or R₂ and R₃, taken together with the nitrogen atom theyare linked to, form a saturated, optionally substituted, heterocyclicring, containing one to two further heteroatoms independently selectedfrom nitrogen, oxygen and sulfur;

either with a compound of formula (VI)ZnX₂   (VI)

wherein X is as defined above;

or with a compound of formula (VIa)B(OR′₄)₃   (VIa)

wherein each R′₄ is independently C₁-C₆ alkyl,

and, if desired, the subsequent hydrolysis of the resulting boronicester of formula (II).

The term “protecting group R” means a tetrazole ring protecting groupknown in the art, preferably a straight or branched C₁-C₆ alkyl,optionally substituted with one or more phenyl groups, in their turnoptionally substituted, for example with C₁-C₄ alkoxy or C₁-C₄alkylthio. Preferred examples of R are tert-butyl, para-methoxybenzyl,trityl and 1-methyl-1-phenylethyl, the latter being particularlypreferred.

The term “salifying group R” means, for example, an alkali oralkaline-earth metal, preferably sodium, potassium or magnesium, morepreferably sodium.

When R₂ and R₃ are C₁-C₆ alkyl groups, they are preferably C₃-C₆ alkylgroups, more preferably isopropyl, sec-butyl, tert-butyl, mostpreferably isopropyl.

When R₂ and R₃ are C₃-C₆ cycloalkyl groups, they are preferablycyclopentyl and cyclohexyl.

When R₂ and R₃ are trialkylsilyl groups, they are preferablytrimethylsilyl.

When R₄ is a C₁-C₆ alkyl group, it is preferably a straight or branchedC₁-C₄ alkyl group, more preferably methyl, ethyl propyl, isopropyl,sec-butyl, tert-butyl, most preferably methyl, ethyl or isopropyl.

The term “heterocyclic ring” as defined above preferably meanspiperidine, piperazine, morpholine, pyrrolidine, more preferably2,2,6,6-tetramethylpiperidine.

The reaction of a compound of formula (V) with a compound of formula(VI) or (VIa) is typically carried out in an ether solvent, preferablyethyl ether, dioxane, methyl tert-butyl ether, tetrahydrofuran ormixtures thereof, or mixtures thereof with apolar solvents, preferablyhexane, heptane, cyclohexane, benzene, toluene and xylene, morepreferably tetrahydrofuran. The stoichiometric ratio of a compound offormula (VI) or (VIa) to a compound of formula (V) ranges from approx.1.0 to approx. 5.0, preferably from 1.1 to 3.0. The reaction is carriedout at a temperature ranging from about 20° C. to the reflux temperatureof the reaction mixture. Reaction times depend on the temperature andthe progress of the reaction is monitored by conventional analyticalmethods.

The hydrolysis of a boronic ester of formula (II) to obtain acorresponding compound of formula (II) in which R₄ is hydrogen, can becarried out according to known methods, for example by addition of amineral or organic acid, in particular phosphoric, hydrochloric oracetic acid, to the reaction mixture.

The compounds of formula (II) wherein R is a 1-methyl-1-phenyl-ethylgroup and Y is a —B(OR₄)₂ group, in which R₄ is as defined above, arenovel and are a further object of the invention.

Preferred examples are those in which each R₄ is independently hydrogen,methyl, ethyl or isopropyl.

Particularly preferred are the following compounds:

2-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenylboronic acid;

2-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenylboronic acidmethyl ester; and

2-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenylboronic acidisopropyl ester.

The compounds of formula (V) are novel and are a further object of thepresent invention.

Preferred examples of compounds of formula (V) are:

2-[2-t-butyl-2H-tetrazol-5-yl]-phenyl magnesium diisopropylamide;

2-[2-sodium-2H-tetrazol-5-yl]-phenyl magnesium diisopropylamide;

and

2-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl magnesiumdiisopropylamide,

in particular the latter.

Compounds (V) can be prepared by reaction of compounds of formula (III)

wherein R is as defined above,

with compounds of formula (VII)Mg(NR₂R₃)₂   (VII)

wherein R₂ and R₃ are as defined above.

The reaction between a compound of formula (III) and a compound offormula (VII) is typically carried out in an ether solvent, for exampleethyl ether, dioxane, methyl tert-butyl ether, tetrahydrofuran ormixtures thereof, or mixtures thereof with apolar solvents, preferablyhexane, heptane, cyclohexane, benzene, toluene and xylene, morepreferably tetrahydrofuran. The stoichiometric ratio of a compound offormula (VII) to a compound of formula (III) ranges from approx. 0.5 toapprox. 3.0, preferably from 1.0 to 2.0. The reaction is carried out ata temperature ranging from about 20° C. to the reflux temperature of thereaction mixture, preferably at the reflux temperature. Reaction timesdepend on the temperature, and the progress of the reaction is monitoredby conventional analytical methods. The resulting compound of formula(V), which can optionally be isolated, is then reacted with a compoundof formula (VI) or (VIa).

The compounds of formula (VII) can be obtained according to knownprocesses, for example as described in DE 100 61 317. Preferably, theresulting compounds of formula (VII) are reacted with compounds offormula (III) without being isolated.

A further object of the invention is the use of a compound of formula(V) for the preparation of a compound of formula (I)

or a pharmaceutically acceptable salt thereof, in which Z is anoptionally substituted heterocycle, containing at least one nitrogenatom; or an amido residue.

Preferably, a compound of formula (V) is used for the preparation of acompound of formula (I) in which Z is selected from:

2-butyl-4-chloro-5-hydroxymethyl-imidazol-1-yl;

2-ethoxy-7-carboxy-1H-benzimidazol-1-yl;

2-butyl-1,3-diaza-spiro[4,4]non-1-en-4-on-3-yl and

(S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoylamino,

most preferably 2-butyl-4-chloro-5-hydroxymethyl-imidazol-1-yl.

The preparation of a compound of formula (I) from a compound of formula(II) can be carried out for example according to EP 846117 or WO95/32962.

The following examples further illustrate the invention.

EXAMPLE 1 Preparation of2-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl zinc chloride(II)

A mixture of 2-(1-methyl-1-phenyl-ethyl)-5-phenyl-2H-tetrazole (5.0 g;20.3 mmoles) and magnesium diisopropylamide (0.75 M solution in THF; 40ml) is refluxed for 3 hrs. The mixture is subsequently cooled anddiluted with a zinc chloride solution (5.4 g; 40.0 mmoles) in THF (29ml). The resulting mixture is refluxed for a further 2 hrs.

¹H-NMR analysis, after treatment with deuterated water, evidences aconversion to organo-zinc higher than 96%.

EXAMPLE 2 Preparation of 2-[2-Trityl-2H-tetrazol-5-yl]-phenyl magnesiumdiisopropylamide (V)

A mixture of 1-trityl-5-phenyl-2H-tetrazole (7.9 g; 20.3 mmoles) andmagnesium diisopropylamide (0.75 M solution in THF; 40 ml) is refluxedfor 3 hrs.

¹H-NMR analysis, after treatment with deuterated water, evidences a 67%conversion to organo-magnesium.

EXAMPLE 3 Preparation of 2-[2-t-butyl-2H-tetrazol-5-yl]-phenyl magnesiumdiisopropylamide (V)

A mixture of 1-t-butyl-5-phenyl-2H-tetrazole (4.1 g; 20.3 mmoles) andmagnesium diisopropylamide (0.75 M solution in THF; 40 ml) is refluxedfor 3 hrs. ¹H-NMR analysis, after treatment with deuterated water,evidences a 75% conversion to organo-magnesium.

EXAMPLE 4 Preparation of 2-[2-sodium-2H-tetrazol-5-yl]-phenyl magnesiumdiisopropylamide (V)

A mixture of 5-phenyl-2H-tetrazole sodium salt (3.4 g; 20.3 mmoles) andmagnesium diisopropylamide (0.75 M solution in THF; 40 ml) is refluxedfor 3 hrs.

¹H-NMR analysis, after treatment with deuterated water, evidences a 75%conversion to organo-magnesium.

EXAMPLE 5 Preparation of2-(2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl)-phenyl)-magnesiumisopropylamide (V)

A 2 liters reactor is loaded with 600 ml of a magnesium diisopropylamide0.75 M solution and 100 g of2-(1-methyl-1-phenyl-ethyl)-5-phenyl-2H-tetrazole. The mixture isrefluxed for 4 hrs., then the reaction is seeded with 1 g of2-(2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl)-phenyl)-magnesiumisopropylamide and then refluxed for a further 16 hrs. The resultingmixture is cooled to 20-30° C., filtered by suction under inertatmosphere, then washed with THF to afford 102 g2-(2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl)-phenyl)-magnesiumisopropylamide.

¹H NMR (CD₃OD), (δ, ppm): 8.15 (1H, m); 7.43 (3H, m); 7.31 (3H, m); 7.18(2H, d); 2.91 (2H, set); 2.20 (6H, s); 1.02 (12H, d).

EXAMPLE 6 Preparation of2-(2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl)-phenyl)-boronic acid(II)

A 2 liters reactor is loaded with 102 g2-(2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl)-phenyl)-magnesiumisopropylamide and 250 ml of THF. The suspension is cooled to 0-5° C.and added with 58.3 g of trimethylborate in 20 minutes. The mixture isthen gradually heated to room temperature, left under stirring for atleast 2 hrs., then diluted to pH 2.5-3 with phosphoric acid. Theresulting solution is heated to 30-35° C. and kept at this temperaturefor 2 hrs., then stirring is interrupted and the aqueous phase isdiscarded. 250 ml of water are added to the organic phase and theresulting mixture is concentrated under vacuum to remove THF. Theresulting mixture is diluted with 60 ml of toluene and left understirring at room temperature for at least 3 hrs. The precipitatedproduct is filtered and washed with water and toluene. After drying a60° C. under vacuum, 60 g of2-(2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl)-phenyl)-boronic acidare obtained.

¹H NMR (DMSO d₆), (δ, ppm): 8.00 (2H, s); 7.90 (1H, m); 7.48 (3H, m);7.31 (3H, m); 7.18 (2H, d); 2.15 (6H, s).

EXAMPLE 7 Preparation2-(2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl)-phenyl)-boronic acidmethyl ester (II)

A 2 liters reactor is loaded with 102 g2-(2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl)-phenyl)-magnesiumisopropylamide and 250 ml of THF. The suspension is cooled to 0-5° C.and added with 58.3 g of trimethylborate, in 20 minutes. The mixture isthen gradually heated to room temperature, left under stirring for atleast 2 hrs., then diluted with water and toluene. The aqueous phase isdiscarded and the organic phase is evaporated to a residue. 70 g of anoil consisting of2-(2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl)-phenyl)-boronic acidmethyl ester methyl ester.

¹H NMR (DMSO d₆), (δ, ppm): 7.90 (1H, m); 7.48 (3H, m); 7.31 (3H, m);7.18 (2H, d); 3.17 (6H, s); 2.15 (6H, s).

Following the same procedure,2-(2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl)-phenyl)-boronic acidisopropyl ester is obtained.

1. A process for the preparation of a compound of formula (II)

in which R is hydrogen, a protecting group or a salifying group and Y isa —B(OR₄)₂ group, wherein each R₄ is independently hydrogen or C₁-C₆alkyl; or a —ZnX group, wherein X is a halogen atom selected fromchlorine, bromine and iodine; which comprises the reaction of a compoundof formula (V)

wherein R is as defined above and R₂ and R₃, which can be the same ordifferent, are straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl,trialkylsilyl, or R₂ and R₃, taken together with the nitrogen atom theyare linked to, form a saturated, optionally substituted, heterocyclicring, containing one to two further heteroatoms independently selectedfrom nitrogen, oxygen and sulfur; either with a compound of formula (VI)ZnX₂   (VI) wherein X is as defined above; or with a compound of formula(VIa)B(OR′₄)₃   (VIa) wherein each R′₄ is independently C₁-C₆ alkyl, and, ifdesired, the subsequent hydrolysis of the resulting boranic ester offormula (II).
 2. A process as claimed in claim 1, in which thestoichiometric ratio of a compound of formula (VI) or (VIa) to acompound of formula (V) ranges from 1.0 to 5.0.
 3. A process as claimedin claim 2, in which the stoichiometric ratio of a compound of formula(VI) or (VIa) to a compound of formula (V) ranges from 1.1 to 3.0.
 4. Aprocess as claimed in claim 1, in which the reaction is carried out inan ether solvent or mixtures thereof with an apolar solvent, at atemperature ranging from 20° C. to the reflux temperature.
 5. A processas claimed in claim 1, in which a compound of formula (V) is prepared byreaction between a compound of formula (III)

wherein R is as defined in claim 1, with a compound of formula (VII)Mg(NR₂R₃)₂   (VII) wherein R₂ and R₃ are as defined in claim
 1. 6. Aprocess as claimed in claim 5, in which the stoichiometric ratio of acompound of formula (VII) to a compound of formula (III) ranges from 0.5to 3.0.
 7. A process as claimed in claim 6, in which the stoichiometricratio of a compound of formula (VII) to a compound of formula (III)ranges from 1.0 to 2.0.
 8. A compound of formula (II), as defined inclaim 1, wherein R is a 1-methyl-1-phenyl-ethyl group and Y is a—B(OR₄)₂ group, in which R₄ is as defined in claim
 1. 9. A compound asdefined in claim 8, wherein each R₄ is independently hydrogen, methyl,ethyl or isopropyl.
 10. A compound as defined in claim 8, which is:2-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenylboronic acid;2-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenylboronic acidmethyl ester; or2-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenylboronic acidisopropyl ester.
 11. A compound of formula (V)

wherein R, R₂ and R₃ are as defined in claim
 1. 12. A compound asdefined in claim 11, which is: 2-[2-t-butyl-2H-tetrazol-5-yl]-phenylmagnesium diisopropylamide; 2-[2-sodium-2H-tetrazol-5-yl]-phenylmagnesium diisopropylamide; or2-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl magnesiumdiisopropylamide.
 13. The use of a compound of formula (V), as definedin claim 11, for the preparation of a compound of formula (I)

in which Z is an optionally substituted heterocycle containing at leastone nitrogen atom; or an amido residue; or of a pharmaceuticallyacceptable salt thereof.
 14. The use as claimed in claim 13, wherein inthe compound of formula (I) the residue Z is selected from:2-butyl-4-chloro-5-hydroxymethyl-imidazol-1-yl;2-ethoxy-7-carboxy-1H-benzimidazol-1-yl;2-butyl-1,3-diaza-spiro[4,4]non-1-en-4-on-3-yl and(S)—N-(1-carboxy-2-methylprop-1-yl)-N-pentanoylamino.
 15. A process asclaimed in claim 2, in which the reaction is carried out in an ethersolvent or mixtures thereof with an apolar solvent, at a temperatureranging from 20° C. to the reflux temperature.
 16. The use of a compoundof formula (V), as defined in claim 12, for the preparation of acompound of formula (I)

in which Z is an optionally substituted heterocycle containing at leastone nitrogen atom; or an amido residue; or of a pharmaceuticallyacceptable salt thereof.